The purpose of this K23 Award is to propose a training plan to develop David B. Huang, M.D.,M.P.H. into a successful, independent clinical investigator with a focus on enteric pathogens. Enteroaggregative Escherichia coli (EAEC) is an emerging enteric pathogen with a tremendous amount of genetic diversity. Recent molecular advances have suggested that certain virulence genes such as aggR may be important in EAEC diarrheal illness. Having a large EAEC collection (N = 226) obtained from prospectively established cohorts of U.S. travelers to Guadalajara, Mexico; Goa, India; or Montego Bay, Jamaica, we have a unique opportunity to evaluate the determinants of EAEC virulence in diarrhea illness and the host immune response to EAEC infection. The long-term objectives of this project are: 1) to identify the importance of enterovirulent genes carried by EAEC in diarrheal illness and the associated host immunological response, and 2) to use these genes in the development of novel interventions for the control of EAEC infection. The overall hypothesis of this investigation is that distinct bacterial virulence genes regulate EAEC virulence in humans, and that the aggR regulon is associated with clinical and immunological outcomes of EAEC infection. In order to test this hypothesis, we propose the following specific aims: 1) to study the presence or absence of aggR among EAEC isolates-in adult travelers newly infected with EAEC; 2) to evaluate the intestinal epithelial inflammatory response profile to infection with EAEC carrying aggR', and 3) to determine the humoral and secretory antibody response to infection with EAEC that carry aggR. The results of this grant will provide an increased understanding of the genetic diversity and the pathophysiology of EAEC and their role in determining the clinical and immunological outcomes caused by EAEC. This research will also expand upon the Pi's current skills and past work in an outstanding research and mentoring environment and provide fundamental laboratory and research experience for the development of the PI into a independent clinical investigator dedicated to improving the public health of people at risk of enteric pathogens.